Maintenance and functional regulation of immune memory to COVID-19 vaccines in tissues

Memory T and B cells in lymphoid and mucosal tissues maintain long-term protection, though their generation following vaccination remains challenging to assess in humans. Here, we investigated immune memory generated to COVID-19 mRNA vaccines across blood, lymphoid organs, and lungs from 42 vaccinated organ donors aged 23-86, of whom 57% were previously infected with SARS-CoV-2. Using high-dimensional profiling, we reveal that Spike (S)-reactive memory T cells distribute in lymphoid organs and lungs, variably express tissue resident markers based on infection history, and exhibit site-specific compositions of effector and regulatory memory T cells. S-reactive B cells are mostly class-switched memory cells localized to lymphoid organs correlating with circulating antibodies. Importantly, tissue memory T cells are more stably maintained post-vaccination and over age and exhibit a bias towards regulatory cell functional profiles compared to circulating populations. Our results show that mRNA vaccines can induce heterogeneous memory populations across sites for protection and controlling immune pathology. We performed CITE-seq on immune cell populations from human blood and different human organ donor tissues in response to SARS-COV2 and influenza peptide pool stimulation and DMSO controls.